Peptide bicycles that inhibit the Grb2 SH2 domain.
Peptide bicycles that inhibit the Grb2 SH2 domain.
复制标题
DOI：
10.1002/cbic.201200175
复制
发表时间：
2012-07-09
期刊：
影响因子：
3.2
通讯作者：
Kritzer, Joshua A.
中科院分区：
文献类型：
--
作者：
Quartararo, Justin S.;Wu, Pianpian;Kritzer, Joshua A.
将短肽开发成有用的探针和治疗先导物仍然是一个困难的挑战。结构硬化是一种经过验证的改善短肽性质的方法。在这项工作中，我们报告了一种稳定肽大环的策略，通过引入侧链对侧链的钉合物，产生具有更高亲和力，选择性和抗降解性的肽自行车。我们已经将这种策略应用于G1，一个11个残基的肽大环，结合生长因子结合蛋白2（Grb2）的Src同源2（SH2）结构域。几个同源肽双环合成完全在树脂上以高产率。两轮迭代设计产生了肽双环BC1，其效力是G1的60倍，选择性是G1的200倍。此外，BC1在缓冲的人血清中24小时后是完全完整的，在此条件下G1完全降解。我们的肽自行车方法有望开发SH2结构域和其他pTyr结合蛋白的选择性抑制剂，以及许多其他蛋白质-蛋白质相互作用的抑制剂。
Developing short peptides into useful probes and therapeutic leads remains a difficult challenge. Structural rigidification is a proven method for improving the properties of short peptides. In this work, we report a strategy for stabilizing peptide macrocycles by introducing side-chain-to-side-chain staples, producing peptide bicycles with higher affinity, selectivity, and resistance to degradation. We have applied this strategy to G1, an 11-residue peptide macrocycle that binds the Src homology 2 (SH2) domain of growth-factor-bound protein 2 (Grb2). Several homodetic peptide bicycles were synthesized entirely on-resin with high yields. Two rounds of iterative design produced peptide bicycle BC1, which is 60-fold more potent than G1 and 200-fold more selective. Also, BC1 is completely intact after 24 hours in buffered human serum, conditions under which G1 is completely degraded. Our peptide bicycle approach holds promise for the development of selective inhibitors of SH2 domains and other pTyr-binding proteins, as well as inhibitors of many other protein-protein interactions.
登录
查看更多内容
影响因子：
7.8
作者：
Bauer, Renato A.;Wurst, Jacqueline M.;Tan, Derek S.
通讯作者：
Tan, Derek S.
影响因子：
14.8
作者：
Heinis, Christian;Rutherford, Trevor;Winter, Greg
通讯作者：
Winter, Greg
DOI：
10.1073/pnas.0504613102
发表时间：
2005-09-27
影响因子：
11.1
作者：
Clark, RJ;Fischer, H;Craik, DJ
通讯作者：
Craik, DJ
影响因子：
16.6
作者：
Clark, Richard J.;Jensen, Jonas;Craik, David J.
通讯作者：
Craik, David J.
影响因子：
4
作者：
Angelini, Alessandro;Cendron, Laura;Heinis, Christian
通讯作者：
Heinis, Christian